Neuroscience Letters 402 (2006) 267–272 Exaggeration of tissue trauma induces signs and symptoms of acute CRPS I, however displays distinct differences to experimental CRPS II Georg Gradl a,b , Susanne Gaida b , Burkhard Finke b , Philip Gierer a,b , Thomas Mittlmeier a , Brigitte Vollmar b,∗ a Department of Trauma and Reconstructive Surgery, University of Rostock, Germany b Department of Experimental Surgery, University of Rostock, Schillingallee 70, 18055 Rostock, Germany Received 15 February 2006; received in revised form 5 April 2006; accepted 12 April 2006 Abstract As CRPS I frequently develops after tissue trauma, we proposed that an exaggerated inflammatory response to tissue trauma may underlie CRPS I. Therefore, we studied the vascular inflammatory, nociceptive and apoptotic sequelae of (i) soft tissue trauma and (ii) exaggerated soft tissue trauma in comparison to those of (iii) sciatic nerve chronic constriction injury, modeling CRPS II. Standardized soft tissue trauma (TR) was induced by means of a controlled impact injury technique in the hind limb of pentobarbital-anesthetized rats. Additional animals received soft tissue trauma and femoral arterial infusion of mediator-enriched supernatant achieved by homogenization and centrifugation of traumatized muscle tissue in order to provoke an exaggerated trauma response (ETR). Infusion of supernatant of non-traumatized muscle served as control intervention (STR, sham trauma response). Neuropathy was induced by chronic constriction injury of the sciatic nerve (CCI). Untreated animals served as controls (CO). Detailed nociceptive testing showed temporarily decreased mechanical pain thresholds in ETR animals that resolved within 14 days, while TR and STR animals, i.e. those with singular limb trauma, and controls remained free of pain. Neither cold- nor heat-evoked allodynia developed in post-traumatic animals, whereas CCI animals presented the well-known pattern of ongoing neuropathic pain. Using high-resolution in vivo multifluorescence microscopy, muscle tissue of traumatized animals revealed an enhanced inflammatory response that was found most pronounced in ETR animals. CCI of the sciatic nerve was not accompanied by tissue inflammation; however, induced myocyte apoptosis. Collectively, these data indicate that exaggeration of trauma response induces signs and symptoms of acute CRPS I. Pain perception displays differences to that in CRPS II. Apoptosis turns out to be a distinctive marker for CRPS, warranting further evaluation in clinical studies. © 2006 Elsevier Ireland Ltd. All rights reserved. Keywords: Microcirculation; CRPS; Inflammation; Leukocyte–endothelial cell interaction; Apoptosis; Pain; Trauma CRPS I develops after tissue trauma displaying clinical signs and symptoms reminiscent of those induced by the injury itself; however, more pronounced and long-lasting [10,19]. Neverthe- less a detailed knowledge of physiological tissue response to trauma is mandatory in order to clearly differentiate the physi- ological trauma reaction from a possible pathological response as it is seen in CRPS I. Recent animal models employing tis- sue trauma in order to imitate human CRPS I substantiate the idea of CRPS I being an abnormal post-traumatic inflammatory reaction [4,12]. An exaggeration of inflammatory post-traumatic ∗ Corresponding author. Tel.: +49 381 494 6220; fax: +49 381 494 6222. E-mail address: brigitte.vollmar@med.uni-rostock.de (B. Vollmar). response underlying CRPS I was first hypothesized by the Hamburg surgeon Paul Sudeck and revitalized by Goris [7,21]. According to Goris the local inflammation of CRPS I patients may be traced back to an enhanced mediator action [7]. Recently we demonstrated that not only mechanical tissue trauma but also local intra-arterial administration of trauma mediators without mechanical injury induced inflammation, mechanical pain and myocyte apoptosis [8]. Therefore, this study induces an exaggeration of post- traumatic inflammatory response by the combination of stan- dardized tissue trauma and local intra-arterial infusion of trauma mediators, introducing a novel approach for modeling CRPS I. Detailed analysis of pain perception as well as tissue inflam- mation and apoptosis using in vivo high-resolution multiflu- 0304-3940/$ – see front matter © 2006 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.neulet.2006.04.007